CUTANEOUS ONCOLOGY

这是MD安德森癌症中心医学教授兼皮肤科主任Madeleine Duvic的中期职业发展奖申请。 它将支持皮肤肿瘤学的一个新项目，并使她能够指导该领域的新助理教授，研究员，居民和医学生。 申请人在开展以患者为导向的临床研究方面有着出色的记录，并且是开发治疗皮肤T细胞淋巴瘤（CTCL）的新疗法的领导者。 有一个坚定不移的承诺，以病人为导向的研究和指导在职业发展的各个层面的行为。 该奖项将使申请人从目前的临床职责中解脱出来，使她能够将60%以上的时间用于以患者为导向的翻译类维生素A研究和指导活动。 临床研究课程，肿瘤学研究员研讨会系列和机构会议将促进申请人和学生的进一步职业发展。 两个转化研究项目提出了使用类维生素A的癌症。 1]一种新的II类肿瘤抑制因子他扎罗汀诱导基因3（TIG-3）的缺失将在非黑色素瘤皮肤癌的发生和进展中进行研究。 与配对的正常皮肤相比，TIG-3在侵袭性皮肤癌与非侵袭性皮肤癌中以及在基底癌和鳞状癌中显著降低的发现将在更大组的样品中并通过cDNA测序和杂合性缺失研究来检查。侵袭性肿瘤患者口服Accutane辅助治疗可能与TIG-3的上调有关。 2]将在CTCL的局部和口服治疗中评估Targretin（一种实验性RXR选择性类维生素A，Targretin）的分子标志物的开发。 Targretin可通过改变细胞因子和促进淋巴细胞浸润的凋亡来恢复表皮中RAR和RXR受体的表达。 治疗前后患者的皮肤病变将使用免疫组织化学和原位杂交研究类维生素A受体，细胞因子和fas/fas配体。 将使用基因组展示探索类维生素A治疗后大细胞进展和基因表达的遗传基础，并将加强分子生物学方面的培训。 了解皮肤癌和CTCL的生物学和新的治疗药物的机制应该导致更好和更少的毒性治疗癌症的发展。 年轻的医生和学生谁接受先进的培训，在适当的检测，预防和治疗皮肤癌将是一种资源，并可能改善未来的患者的结果。

This is a mid-career development award application for Madeleine Duvic, Professor of Medicine and Chief of Dermatology at the MD Anderson Cancer Center. It would support a new program in Cutaneous Oncology and enable her to mentor new Assistant Professors, fellows, residents, and medical students in the field. The applicant has an outstanding track record in conducting patient oriented clinical research and is a leader in developing new therapies for the treatment of Cutaneous T Cell Lymphomas (CTCL). There is an unwavering commitment to the conduct of patient oriented research and mentoring at all levels of career development. The award would free the applicant from half of her current clinical duties, allowing her to spend greater than 60 percent of her time on patient oriented translational retinoid research and mentoring activities. A Clinical Research curriculum, an oncology fellows seminar series, and institutional conferences will enhance further career development of the applicant and students. Two translational research projects are proposed using retinoids for cancer. 1] The loss of a novel class II tumor suppressor, Tazarotene Induced Gene 3 (TIG-3), will be investigated in the development and progression of non-melanoma skin cancers. The finding that TIG-3 is significantly decreased in aggressive versus non-aggressive skin cancer and in basal and squamous carcinomas, compared to paired normal skin will be examined in a larger set of samples and by sequencing cDNAs and by loss of heterozygosity studies. Oral Accutane adjuvant therapy for patients with aggressive tumors may be related to upregulation of TIG-3. 2] Development of molecular markers for Targretin, an experimental RXR selective retinoid, Targretin, will be assessed in the topical and oral treatment of CTCL. Targretin may restore expression of RAR and RXR receptors in epidermis, by altering cytokines and fostering apoptosis of the lymphocytic infiltrates. Patient's skin lesions before and after therapy will be studied using immunohistochemistry and in situ hybridization for retinoid receptors, cytokines, and fas/fas ligand. Genetic basis of large cell progression and gene expression following retinoid therapy will be explored using genomic display and will enhance the training in molecular biology. Understanding the biology of skin cancer and CTCL and the mechanism of novel therapeutic agents should result in the development of better and less toxic therapies for cancer. Young physicians and students who receive advanced training in the proper detection, prevention, and treatment of skin cancers will be a resource and may improve outcomes for patients of the future.